BETA 2-ADRENERGIC RECEPTOR AGONISTS

Description

BACKGROUND OF THE INVENTION

Field of the Invention

[0001] This invention relates to novel multibinding compounds (agents) that are β2 adrenergic receptor agonists and pharmaceutical compositions comprising such compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of respiratory diseases such as asthma and chronic bronchitis. They are also useful in the treatment of nervous system injury and premature labor.

References

[0002] The following publications are cited in this application as superscript numbers:

¹ Hardman, J. G., et al. "The Pharmacological Basis of Therapeutics", McGraw-Hill, New York, (1996)

² Strosberg, A. D. "Structure, Function, and Regulation of Adrenergic Receptors" Protein Sci. 2, 1198-1209 (1993).

³ Beck-Sickinger, A. G. "Structure Characterization and Binding Sites of G-Protein-coupled Receptors" DDT, 1, 502-513, (1996).

⁴ Hein, L. & Kobilka, B. K. "Adrenergic Receptor Signal Transduction and Regulation" Neuropharmacol, 34, 357-366, (1995).

⁵ Strosberg, A. D. & Pietri-Rouxel, F. "Function, and Regulation of β3-Adrenoceptor" TiPS, 17, 373-381, (1996).

⁶ Barnes, P. J. "Current Therapies for Asthma" CHEST, 111:17S-26S, (1997).

⁷ Jack, D. A. "A way of Looking at Agonism and Antagonism: Lessons from Salbutamol, Salmeterol and other β-Adrenoceptor Agonists" Br. J. Clin. Pharmac. 31, 501-514, (1991).

⁸ Kissei Pharmaceutical Co. Ltd. "2-Amino-1-(4-hydroxy-2-methylphenyl)propanol derivatives" JP-10152460 (Publication date June 9, 1998).

State of the Art

[0003] A receptor is a biological structure with one or more binding domains that reversibly complexes with one or more ligands, where that complexation has biological consequences. Receptors can exist entirely outside the cell (extracellular receptors), within the cell membrane (but presenting sections of the receptor to the extracellular milieu and cytosol), or entirely within the cell (intracellular receptors). They may also function independently of a cell (e.g., clot formation). Receptors within the cell membrane allow a cell to communicate with the space outside of its boundaries (i.e., signaling) as well as to function in the transport of molecules and ions into and out of the cell.

[0004] A ligand is a binding partner for a specific receptor or family of receptors. A ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool.

[0005] The super family of seven transmembrane proteins (7-TMs), also called G-protein coupled receptors (GPCRs), represents one of the most significant classes of membrane bound receptors that communicate changes that occur outside of the cell's boundaries to its interior, triggering a cellular response when appropriate. The G-proteins, when activated, affect a wide range of downstream effector systems both positively and negatively (e.g., ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins, and the like).

[0006] Adrenergic receptors (AR) are members of the G-protein coupled receptors that are composed of a family of three receptor sub-types: α1 _{(A, B, D)} α2 _{(A, B, C)}, and β _(1,2,3).^1-5 These receptors are expressed in tissues of various systems and organs of mammals and the proportions of the α and the β receptors are tissue dependant. For example, tissues of bronchial smooth muscle express largely β2-AR while those of cutaneous blood vessels contain exclusively α-AR subtypes.

[0007] It has been established that the β2-AR sub-type is involved in respiratory diseases such as such as asthma⁶, chronic bronchitis, nervous system injury, and premature labor⁸. Currently, a number of drugs e.g., albuterol, formoteml, isoprenolol, or salmeterol having β2-AR agonist activities are being used to treat asthma. However, these drugs have limited utility as they are either non-selective thereby causing adverse side effects such as muscle tremor, tachycardia, palpitations, and restlesness⁶, or have short duration of action and/or slow onset time of action.⁷ Accordingly, there is a need for β2-selective AR agonists that are fast acting and have increased potency and /or longer duration of action.

[0008] The multibinding compounds of the present invention fulfill this need.

SUMMARY OF THE INVENTION

[0009] This invention is directed to novel multibinding compounds (agents) that are agonists or partial agonists of β2 adrenergic receptor and are therefore useful in the treatment and prevention of respiratory diseases such as asthma and chronic bronchitis. They are also useful in the treatment of nervous system injury and premature labor.

[0010] The compounds according to the present invention may be regarded as examples of compounds of the formula

        L₂X     (I)

where one L is a ligand of general formula

and the other L is a ligand of general formula

        -QAr³

wherein the various substituents have the meanings given hereafter.

[0011] The invention provides a bivalent multibinding compound of Formula (II) or a pharmaceutically acceptable salt thereof:

wherein:

Ar¹ is a phenyl ring of formula (c):

wherein:

R⁴ is hydrogen, alkyl, halo, or alkoxy;

R⁵ is hydrogen, hydroxy, halo, or amino;

R⁶ is hydrogen, halo, hydroxy, alkoxy, substituted alkyl, or -NRC(O)R, wherein each R is hydrogen or alkyl; or Ar¹ is a 2,8-dihydroxyquinolin-5-yl group, which may also be represented by the formula

Ar³ is either:

(i) a phenyl ring of formula (c) as defined above; or

(ii) a phenyl ring of formula (d):

wherein:

R⁷ is hydrogen, alkyl, alkenyl, substituted alkyl, halo, alkoxy, substituted alkoxy, or hydroxy; and

R⁸ is hydrogen, halo, alkoxy, or substituted alkoxy; or

(iii) naphthyl,

where substituted alkyl means hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl, 2-sulfonamidoethyl or 2-carboxyethyl, and substituted alkoxy means (substituted alkyl)-O-;
   W is a bond, or an alkylene chain wherein one or more of the carbon atoms in the alkylene group are optionally replaced by -O-;
   Ar² is phenylene wherein the W and the X groups are attached at the 1,2-, 1,3, and 1,4 positions of the phenyl ring; or cyclohexylene optionally substituted with methyl and wherein the W and the X groups are attached at the 1,3, and 1,4 positions of the cyclohexyl ring;
   X is a covalent bond; and
   Q is -NH-CH₂ -CH(OH)-; -NH-CH(CH₂OH)-; -(CH₂)₃-O-(CH₂)₆-NH-CH₂-CH(OH)-; or -NH-CH₂-CH(OH)-CH₂-O-.

[0012] The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIGs. 1-7 illustrate synthesis of compounds of Formula (II).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0014] This invention is directed to multibinding compounds which are β2 adrenergic receptor agonists, pharmaceutical compositions containing such compounds and methods for treating diseases mediated by β2 adrenergic receptor in mammals. When discussing such compounds, compositions or methods, the following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings.

[0015] The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, n-hexyl, n-decyl, tetradecyl, and the like.

[0016] The term "substituted alkyl" refers to an alkyl group as defined above, having from 1 to 5 substituents, acid preferably I to 3 substituents, selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl, 2-sulfonamidoethyl, and 2-carboxyethyl.

[0017] The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH₂-), ethylene (-CH₂CH₂-), the propylene isomers (e.g., -CH₂CH₂CH₂- and -CH(CH₃)CH₂-) and the like.

[0018] The term "alkoxy" refers to the group alkyl-O-, where alkyl is as defined herein. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0019] The term "substituted alkoxy" refers to the group substituted alkyl-O-, where substituted alkyl is as defined herein.

[0020] The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least I and preferably from 1-6 sites of vinyl unsaturation. Preferred alkenyl groups include ethenyl (-CH=CH₂), n-propenyl (-CH₂CH=CH₂), iso-propenyl (-C(CH₃)=CH₂), and the like.

[0021] The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0022] The term "pharmaceutically-acceptable salt" refers to salts which retain the biological effectiveness and properties of the multibinding compounds of this invention and which are not biologically or otherwise undesirable. In many cases, the multibinding compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

[0023] Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.

[0024] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[0025] The term "pharmaceutically-acceptable cation" refers to the cation of a pharmaceutically-acceptable salt.

[0026] The term "pseudohalide" refers to functional groups which react in displacement reactions in a manner similar to a halogen. Such functional groups include, by way of example, mesyl, tosyl, azido and cyano groups.

[0027] The term "protecting group" or "blocking group" refers to any group which when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group (See., T.W. Greene and P.G.H. Wuts, "Protective Groups in Organic Synthesis", 2^nd Ed.). The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyldiphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product. Preferred removable thiol blocking groups include disulfide groups, acyl groups, benzyl groups, and the like.

[0028] Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxy-carbonyl (FMOC), allyloxycarbonyl (ALOC), and the like which can be removed by conventional conditions compatible with the nature of the product.

[0029] Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild conditions compatible with the nature of the product.

[0030] The term "optional" or "optionally" means that the subsequently described event, circumstance or substituent may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0031] The term "ligand" or " ligands" as used herein denotes a compound that is a binding partner for a β2 adrenergic receptor and is bound thereto by complementarity. Preferred ligands are those that are either β2 adrenergic receptor agonist or antagonist. The specific region or regions of the ligand that is (are) recognized by the receptor is designated as the "ligand domain". A ligand may be either capable of binding to the receptor by itself, or may require the presence of one or more non-ligand components for binding (e.g., Ca⁺², Mg⁺² or a water molecule is required for the binding of a ligand to various ligand binding sites). Examples of ligands useful in this invention are described herein. Those skilled in the art will appreciate that portions of the ligand structure that are not essential for specific molecular recognition and binding activity may be varied substantially, replaced or substituted with unrelated structures (for example, with ancillary groups as defined below) and, in some cases, omitted entirely without affecting the binding interaction. The primary requirement for a ligand is that it has a ligand domain as defined above. It is understood that the term ligand is not intended to be limited to compounds known to be useful in binding to β2 adrenergic receptor (e.g., known drugs). Those skilled in the art will understand that the term ligand can equally apply to a molecule that is not normally associated with β2 adrenergic receptor binding properties. In addition, it should be noted that ligands that exhibit marginal activity or lack useful activity as monomers can be highly active as multivalent compounds because of the benefits conferred by multivalency.

[0032] The term "ligand" or " ligands" as used herein is intended to include the racemic forms of the ligands as well as individual enantiomers and diasteromers and non-racemic mixtures thereof.

[0033] The term "potency" refers to the minimum concentration at which a ligand is able to achieve a desirable biological or therapeutic effect. The potency of a ligand is typically proportional to its affinity for its ligand binding site. In some cases, the potency may be non-linearly correlated with its affinity. In comparing the potency of two drugs, e.g., a multibinding agent and the aggregate of its unlinked ligand, the dose-response curve of each is determined under identical test conditions (e.g., in an in vitro or in vivo assay, in an appropriate animal model such a human patient). The finding that the multibinding agent produces an equivalent biological or therapeutic effect at a lower concentration than the aggregate unlinked ligand is indicative of enhanced potency.

[0034] The term "selectivity" or "specificity" is a measure of the binding preferences of a ligand for different ligand binding sites (receptors). The selectivity of a ligand with respect to its target ligand binding site relative to another ligand binding site is given by the ratio of the respective values of K_d (i.e., the dissociation constants for each ligand-receptor complex) or, in cases where a biological effect is observed below the K_d, the ratio of the respective EC₅₀'s (i.e., the concentrations that produce 50% of the maximum response for the ligand interacting with the two distinct ligand binding sites (receptors)).

[0035] The term "ligand binding site" denotes the site on the β-adrenergic receptor that recognizes a ligand domain and provides a binding partner for the ligand. The ligand binding site may be defined by monomeric or multimeric structures. This interaction may be capable of producing a unique biological effect, for example, agonism, antagonism, and modulatory effects or it may maintain an ongoing biological event, and the like.

[0036] It should be recognized that the ligand binding sites of the receptor that participate in biological multivalent binding interactions are constrained to varying degrees by their intra- and inter-molecular associations. For example, ligand binding sites may be covalently joined to a single structure, noncovalently associated in a multimeric structure, embedded in a membrane or polymeric matrix, and so on and therefore have less translational and rotational freedom than if the same structures were present as monomers in solution.

[0037] The terms "agonism" and "antagonism" is well known in the art. The term "modulatory effect" refers to the ability of the ligand to change the activity of an agonist or antagonist through binding to a ligand binding site.

[0038] The term "inert organic solvent" or "inert solvent" means a solvent which is inert under the conditions of the reaction being described in conjunction therewith including, by way of example only, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, t-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert solvents.

[0039] The term "treatment" refers to any treatment of a pathologic condition in a mammal, particularly a human, and includes:

(i) preventing the pathologic condition from occurring in a subject which may be predisposed to the condition but has not yet been diagnosed with the condition and, accordingly, the treatment constitutes prophylactic treatment for the disease condition;

(ii) inhibiting the pathologic condition, i.e., arresting its development;

(iii) relieving the pathologic condition, i.e., causing regression of the pathologic condition; or

(iv) relieving the conditions mediated by the pathologic condition.

[0040] The term "pathologic condition which is modulated by treatment with a ligand" covers all disease states (i.e., pathologic conditions) which are generally acknowledged in the art to be usefully treated with a ligand for the β2-adrenergic receptor in general, and those disease states which have been found to be usefully treated by a specific multibinding compound of our invention. Such disease states include, by way of example only, the treatment of a mammal afflicted with asthma, chronic bronchitis, and the like.

[0041] The term "therapeutically effective amount" refers to that amount of multibinding compound which is sufficient to effect treatment, as defined above, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated; the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

Representative Compounds of Formula (II):

[0042] 
I. Representative bivalent multibinding compounds of Formula (II) wherein Ar¹ is 4-hydroxy-3-hydroxymethylphenyl, Ar² is 1,4-phenylene, X, W, Q, and Ar³ are as defined in Table A below are:

Table A

Cpd. #	Stereochem. at *C	W	X	-Q-Ar3 (** = stereochem)
1A	(RS)	-(CH2)2-	bond	-NH-CH2-** CH(OH)phenyl ** = (S)
2A	(RS)	-(CH2)2-	bond	-NH-CH2-** CH(OH)phenyl ** = (R)
3A	(RS)	-(CH2)2-	bond	-NH-CH2-** CH(OH)phenyl ** = (RS)
4A	(RS)	-(CH2)2-	bond	-NH-CH2-** CH(OH)-(4-hydroxy-3-hydroxy-methyl)phenyl ** = (RS)
5A	(RS)	-(CH2)6O-	bond	-(CH2)3-O -(CH2)6-NH-CH2-** CH(OH)-(4-hydroxy-3-hydroxyethyl)phenyl ** = (RS)
6A	(RS)	-CH2-	bond	-NH-CH2-** CH(OH)-(4-hydroxy-3-hydroxy-methyl)phenyl ** = (RS)
7A	(R)	-(CH2)2-	bond	-NH-CH2-** CH(OH)phenyl ** = (S)
8A	(R)	-(CH2)2-	bond	-NH-CH2-** CH(OH)phenyl ** = (R)
11A	(RS)	-(CH2)2-	bond	-NH-CH2-** CH(OH)-O-naphth-1-yl ** = (RS)

III. Representative bivalent multibinding compounds of Formula (II) wherein Ar¹ is 4-hydroxy-3-hydroxy-methylphenyl, Ar³ is (4-hydroxy-3-hydroxymethyl)phenyl, X, W, Q, and Ar² are as defined in Table C below are:

Table C

Cpd. #	Stereochem. at *C	W	X	Ar2	Q
1C	(RS)	bond	bond	trans-1,4-cyclohexane	-NH-CH2-** CH(OH)-** = (RS)

V. Representative bivalent multibinding compounds of Formula (II) wherein Ar¹ is phenyl, W is -(CH₂)₂-, and Ar² is 1,4-phenylene and-Q-Ar³, is [2-hydroxy-2-phenyl]ethylamino, and X is a bond are as shown in Table E below:

Table E

Cpd. #	Stereochem. at *C	Stereochem. at **C
1E	(RS)	(RS)
2E	(R)	(S)
3E	(R)	(R)

PREFERRED EMBODIMENTS

[0043] While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (II) are preferred.

[0044] When Ar¹ is a phenyl ring of formula (c):

   R⁴ is preferably hydrogen, methyl, fluoro, chloro, or methoxy;
   R⁵ is preferably hydrogen, hydroxy, fluoro, chloro, or amino; and
   R⁶ is preferably hydrogen, chloro, fluoro, hydroxy, methoxy, hydroxymethyl, or -NHCHO.
   W is preferably a covalent bond, methylene, ethylene, propylene, -(CH₂)₆-O-(CH₂)₃-, or -(CH₂)₆-O; and
   Ar² is preferably 1,4-phenylene.
   Q is -NH-CH₂-*CH(OH)-; -NH-*CH(CH₂OH)-; -(CH₂)₃-O-(CH₂)₆-NH-CH₂-*CH(OH)-; or -NH-CH₂-*CH(OH)-CH₂-O- (where * is R or S stereochemistry).

[0045] Within the above preferred, more preferred group of compounds, a particularly preferred group of compounds is that wherein:

(i) Ar³ is same as Ar¹ as defined in preferred embodiments above.
Another particularly preferred group of compounds is that wherein:

(ii) Ar³ is a phenyl ring of formula (d):

wherein:

R⁷ is hydrogen, alkyl, alkenyl, substituted alkyl, halo, alkoxy, substituted alkoxy, or hydroxy, preferably hydrogen, methyl, propen-2-yl, fluoro, chloro, methoxy, or hydroxy; and

R⁸ is hydrogen, halo, alkoxy, or substituted alkoxy, preferably hydrogen, fluoro, chloro, or methoxy.

(iii) Yet another particularly preferred group of compounds is that wherein Ar³ is naphthyl.

[0046] Within the above preferred, more preferred, and particularly preferred groups, even more particularly preferred group is that wherein:

Ar¹ is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-dichlorophenyl, 2-chloro-3,4-dihydroxyphenyl, 2-fluoro-3,4-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3-(HCONH-)phenyl, 3-chlorophenyl, 2,5-dimethoxyphenyl, 3,5-dichloro-4-aminophenyl, or

preferably 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3-(HCONH-)phenyl, 3,5-dichloro-4-aminophenyl, or

and
   Ar³ is:





   preferably, phenyl or 4-hydroxy-3-hydroxymethylphenyl.

GENERAL SYNTHETIC SCHEME

[0047] Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.

[0048] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie, or Sigma (St. Louis, Missouri, USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0049] The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0050] Furthermore, it will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0051] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0052] These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.

Preparation of a multibinding compound of Formula (I)

[0053] In general, a bivalent multibinding compound of Formula (I) can be prepared as illustrated and described in Schemes A-D below.

[0054] A bivalent multibinding compound of Formula (I) can be prepared by covalently attaching the ligands, L, as defined in the Summary of the Invention, as shown in Scheme A below.

[0055] In method (a), a bivalent multibinding compound of Formula (I) is prepared in one step, by covalently attaching the ligands, L, where FG¹ and FG² represent a functional group such as halo, amino, hydroxy, thio, aldehyde, ketone, carboxy, carboxy derivatives such as acid halide, ester, amido, and the like. This method is preferred for preparing compounds of Formula (I) where the ligands are the same.

[0056] In method (b), the compounds of Formula (I) are prepared in a stepwise manner by covalently attaching one equivalent of a ligand, L₁, where FG¹ and FG² represent a functional group as defined above, and FG²PG is a protected functional group to give an intermediate of formula (II). Deprotection of the second functional group on the ligand, followed by reaction with a ligand L₂, which may be same or different than ligand L₁, then provides a compound of Formula (I). This method is suitable for preparing compounds of Formula (I) where the ligands are the non-identical.

[0057] The ligands are covalently attached using conventional chemical techniques providing for covalent linkage. Reaction chemistries resulting in such linkages are well known in the art and involve the use of complementary functional groups as shown in Table I below.

Table I

Representative Complementary Binding Chemistries
First Reactive Group	Second Reactive Group	Linkage
carboxyl	amine	amide
sulfonyl halide	amine	sulfonamide
hydroxyl	alkyl/aryl halide	ether
hydroxyl	isocyanate	urethane
amine	epoxide	β-hydroxyamine
amine	alkyl/aryl halide	alkylamine
amine	isocyanate	urea
hydroxyl	carboxyl	ester
amine	aldehyde	amine

[0058] Reaction between a carboxylic acid and a primary or secondary amine in the presence of suitable, well-known activating agents such as dicyclohexylcarbodiimide, results in formation of an amide bond; reaction between an amine group and a sulfonyl halide, in the presence of a base such as triethylamine, pyridine, and the like results in formation of a sulfonamide bond; and reaction between an alcohol or phenol group and an alkyl or aryl halide in the presence of a base such as triethylamine, pyridine, and the like, results in formation of an ether bond.

[0059] A bivalent multibinding compound of Formula (II) where Ar³ is the same as Ar¹, X is a bond, and Q is 2-hydroxyethylamino group, can be prepared from an acetophenone derivative of formula 1 as shown in Scheme B below.

[0060] Condensation of an acetophenone derivative of formula 1 with a diamine of formula 2 in an ethereal solution such as tetrahydrofuran provides an imine of formula 3. Reduction of the imine with a suitable reducing agent such as borane provides a compound of Formula (II). Suitable reaction solvents are tetrahydrofuran, and the like. Compound 1 where Ar¹ is phenyl is prepared by heating acetophenone in 48% hydrobromic acid in dimethylsulfoxide.

[0061] Compounds of formula 1 can be prepared by methods well known in the art. For example, α,α-dihydroxy- 4-hydroxy-3-methoxycarbonylacetophenone can be prepared by heating 5-acetylsalicylic acid methyl ester in 48% hydrobromic acid.

[0062] Alternatively, a bivalent multibinding compound of Formula, (II) where Ar³ is the same as Ar¹, X is a bond, and Q is 2-hydroxyethylamino group, can be prepared from an acetophenone derivative of formula 1 as shown in Scheme C below.

[0063] A compound of Formula (II) can be prepared by reacting an epoxide of formula 4 with a diamine of formula 2. Epoxides 4 are either commercially available or they can be prepared by the methods described in Kierstead, R.W. et. Al. J. Med. Chem. 26, 1561-1569, (1983) or Hett, R. et. Al. Tet. Lett.35, 9345-9348 (1994).

[0064] Another method of preparing a bivalent multibinding compound of Formula (II) where the second ligand Ar³ is the same as Ar¹, X is a bond, and Q is 2-hydroxyethylamino group, uses an (acetophenone derivative of formula 5 as shown in Scheme D below.

[0065] Bromination of an acetophenone derivative of formula 5 with bromine in a halogenated organic solvent such as chloroform provides an α-bromoacetophenone derivative of formula 6. Treatment of 6 with sodium azide followed by reduction of the resulting azide 7 with a suitable reducing agent such as lithium aluminum hydride provides ethanolamine derivative of formula 8. Condensation of 2 equivalents of 8 with a dialdehyde compound 9 provides an imine of formula 10 which is converted to a compound of Formula (II) as described in Scheme A above.

Utility, Testing, and Administration

Utility

[0066] The multibinding compounds of this invention are β2 adrenergic receptor agonists. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of diseases mediated by β2 adrenergic receptor such as asthma, bronchitis, and the like. They are also useful in the treatment of nervous system injury and premature labor. It is also contemplated that the compounds of this invention are useful for treating metabolic disorders such as obesity, diabetes, and the like.

Testing

[0067] The β2 adrenergic receptor agonistic activity of the compounds of formula (I) to may be demonstrated by a variety of in vitro assays known to those of ordinary skill in the art, such as the assay described in the biological examples 1 and 2. It may also be assayed by the Ex vivo assays described in Ball, D. I. et al., "Salmterol a Novel, Long-acting beta 2-Adrenergic Agonist: Characterization of Pharmacological Activity in Vitro and in Vivo" Br. J. Pharmacol., 104, 665-671 (1991); Linden, A. et al., "Sameterol, Formaterol, and Salbutamol in the Isolated Guinea-Pig Trachea: Differences in Maximum Relaxant Effect and Potency but not in Functional Atagonism. Thorax, 48, 547-553, (1993); and Bials, A. T. et al., Inventigations into Factors Determining the Duration of Action of the Beta 2-Adrenoceptor Agonist, Salmateroal. Br. J. Pharmacol., 108, 505-515 (1993); or in vivo assays such as those described in Ball, D. I. et al., "Salmterol a Novel, Long-acting beta 2-Adrenergic Agonist: Characterization of Pharmacological Activity in Vitro and in Vivo" Br. J. Pharmacol., 104, 665-671 (1991); Kikkawa, H. et al., "RA-2005, a Novel, Long-acting, and Selective Beta 2-Adrenoceptor Agonist: Characterization of its in vivo Bronchodilating Action in Guinea Pigs and Cats in Comparison with other Beta 2-Agonists". Biol. Pharm. Bull., 17, 1047-1052, (1994); and Anderson, G. P., "Formeterol: Pharmacology, Colecular basis of Agonism and Mechanism of Long Duration of a Highly Potent and Selective Beta 2-Adrenoceptor Agonist Bronchodilator, Life Sciences, 52, 2145-2160, (1993).

Pharmaceutical Formulations

[0068] When employed as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as injectable inhaled and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

[0069] This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds described herein associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0070] In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

[0071] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[0072] The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.001 to about 1 g, more usually about 1 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of Formula (I) above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).

[0073] The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0074] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

[0075] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0076] The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0077] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

EXAMPLES

[0078] The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention.

[0079] In the examples below, the following abbreviations have the following meanings. Unless otherwise stated, all temperatures are in degrees Celsius. If an abbreviation is not defined, it has its generally accepted meaning.

Δ =

Angstroms

cm =

centimeter

DCC =

dicyclohexyl carbodiimide

DMF =

N,N-dimethylformamide

DMSO =

dimethylsulfoxide

g =

gram

HPLC =

high performance liquid chromatography

MEM =

minimal essential medium

mg =

milligram

MIC =

minimum inhibitory concentration

min =

minute

mL =

milliliter

mm =

millimeter

mmol =

millimol

N =

normal

THF =

tetrahydrofuran

µL =

microliters

Φm =

microns

rt =

room temperature

R_f =

retention faction

NMR =

nuclear magnetic resonance

ESMS =

electrospray mass spectrum

ppm =

parts per million

Synthetic Examples

Example 1

Synthesis of trans-1,4-bis{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}cyclohexane (following figure 1)

[0080] 

Step I

[0081] To a solution of 5-acetylsalicylic acid methyl ester 11 (5.0g, 25.7 mmole) in dimethylsulfoxide (44 mL) was added 48% hydrobromic acid. The resulting mixture was stirred at 55 °C for 24 h, and poured into a slurry of ice-water (~200 mL), precipitating a pale yellow solid. The solid was filtered, washed with water (200 mL), and dried to give α,α-dihydroxy-4-hydroxy-3-methoxycarbonyl-acetophenone 12. The product was re-suspended in ethyl ether (~200 mL), filtered and dried to give (3.41 g, 59%) of pure product. R_f= 0.8 (10% MeOH/CH₂Cl₂).

[0082] H¹-NMR (4/1 CDCl₃/CD₃OD, 299.96 MHz): δ (ppm) 8.73-8.72 (d, 1H), 8.28-8.24 (dd, 1H), 7.08-7.05 (d, 1H), 5.82 (s, 1H), 4.01 (s, 3H).

Step 2

[0083] To a suspension of α,α-dihydroxy-4-hydroxy-3-methoxycarbonyl-acetophenone 12 (0.3 g, 1.33 mmole) in THF (10 mL) was added a solution of trans-1,4-diaminocyclohexane (76 mg, 0.66 mmole) in THF (5 mL). The resulting suspension was stirred for 3 h at ambient temperature under nitrogen atmosphere, at which formation of an imine was completed judged by TLC analysis. After cooling of the resulting solution at ice bath, an excess amount of 2M BH₃-Me₂S in hexane (4 mL, 8 mmole) was added to the previous solution. The resulting mixture was slowly warmed to rt and refluxed for 4 h under N₂ stream. After cooling the reaction mixture, MeOH (5 mL) was added to quench excess amount of 2M BH₃-Me₂S. After stirring for 30 min., the final solution (or cloudy solution) was evaporated in vacuo, yielding a pale brown solid. The solid was washed with EtOAc/hexane (1/2; 20 mL), and dried. The crude product was dissolved in 50% MeCN/H₂O containing 0.5% TFA, and purified by prep-scale high performance liquid chromatography (HPLC) using a linear gradient (5% to 50% MeCN/H₂O over 50 min, 20 mL/min; detection at 254 nM). Fractions with UV absorption were analyzed by LC-MS to isolate trans-1,4-bis{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}cyclohexane 13.

[0084] H¹-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.35 (d, 2H), 7.18 (dd, 2H), 6.80-6.78 (d, 2H), 4.88-4.86 (m, 2H), 4.65 (s, 4H), 3.15 (br s, 4H), 2.89 (m, 2H), 1.68-1.55 (br m, 4H); ESMS (C₂₄H₃₄N₂O₆): calcd. 446.5, obsd. 447.5 [M+H]⁺.

Compound 16:

[0085] Proceeding as described above but substituting trans-1,4-diamino-cyclohexane with 1,8-diamino-p-menthane gave 1,8-bis{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}-p-menthane. ESMS (C₂₈H₄₂N₂O₆): calcd. 502.6, obsd. 503.3 [M+H]⁺.

Compound 20:

[0086] Proceeding as described above but substituting trans-1,4-diamino-cyclohexane with 2-aminobenzylamine gave 1-{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]aminomethyl}-2-{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]benzene. ESMS (C₂₅H₃₀N₂O₆): calcd. 454.5, obsd 455.3 [M+H]⁺.

Compound 21:

[0087] Proceeding as described above but substituting trans-1,4-diamino-cyclohexane with 2-(4-aminophenyl)ethylamine gave 1-{2-[N-2-[(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-2-{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]benzene. ESMS (C₂₆H₃₂N₂O₆): calcd. 468.5, obsd. 469.3 [M+H]⁺.

Compound 23:

[0088] Proceeding as described above but substituting trans-1,4-diamino-cyclohexane with 2-aminobenzylamine gave 1-{N-[2-{4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]aminomethyl}-4-{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}benzene. ESMS (C₂₅H₃₀N₂O₆): calcd. 454.5, obsd. 455.5 [M+H]⁺, 477.3 [M+Na]⁺.

Example 2

Synthesis of 1-{2-[N-2-[(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-{N-[2-phenyl-2-hydroxyethyl]amino]benzene (following figure 2)

[0089] 

[0090] To a suspension of α,α-dihydroxy-4-hydroxy-3-methoxycarbonyl-acetophenone 12, prepared in Example 1, Step 1 above, (0.3 g, 1.33 mmole) in THF (10 mL) was added a solution of 2-(4-aminophenyl)ethylamine 25 (0.181 g, 1.33 mmol) in THF (5 mL). The resulting suspension was stirred for 3 h at ambient temperature under nitrogen atmosphere, followed by addition α,α-dihydroxy-acetophenone 24 (0.2g, 1.32 mmole). The reaction mixture was stirred for 3 h at RT, at which formation of the imine was completed as judged by TLC analysis. The reaction mixture was cooled in an ice bath and an excess amount of 2M BH₃-Me₂S in hexane (9 mL; 18 mmole) was added. The resulting mixture was slowly warmed to rt, and refluxed for 4 h under N₂ stream. After cooling, MeOH (10 mL) was added to quench excess amount of BH₃-Me₂S. After stirring 30 min., at rt, the final solution (or cloudy suspension) was evaporated in vacuo, to give a pale brown solid. The solid was washed with EtOAc/hexane (1/2; 20 mL), and dried. The crude product was dissolved in 50% MeCN/H₂O containing 0.5% TFA, and purified by prep-scale high performance liquid chromatography (HPLC) using a linear gradient (5% to 50% MeCN/H₂O over 50 min, 20 mL/min; detection at 254 nM). Fractions with UV absorption were analyzed by LC-MS to locate 1-{2-[N-2-[(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]-ethyl}-4-{N-[2-phenyl-2-hydroxyethyl]amino]benzene 26. ESMS (C₂₅H₃₀N₂O₄): calcd. 422.5, obsd. 423.3 [M+H]⁺.

Compound 27:

[0091] Proceeding as described above, but substituting α,α-dihydroxy-4-hydroxy-3-methoxycarbonylacetophenone with α,α-dihydroxyacetophenone gave 1-{2-[N-[2-phenyl-2-hydroxyethyl]aminoethyl}-4-[N-(2-phenyl-2-hydroxyethyl)amino]-benzene. ESMS (C₂₄H₂₈N₂O₈): calcd. 376.5, obsd. 377.0 [M+H]⁺.

Example 3

Synthesis of 1-{2-[N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-hydroxyethyl)amino]benzene (following figure 3)

[0092] 

Step 1

[0093] To a solution of 4-(2-aminoethyl)aniline 25 (20 g, 147 mmole) in methanol (250 mL) was added (Boc)₂O (32.4 g, 148 mmole) in methanol (50 mL) at rt. After stirring for 24 h, the reaction mixture was concentrated to dryness to afford a pale yellow oily residue. The oily material solidified slowly; thus it was dissolved in 5% MeOH/CH₂Cl₂, and subsequently applied to flash silica column chromatography (3 to 10% MeOH/CH₂Cl₂). After purification, 4-(N-Boc-2-aminoethyl)aniline 28 was obtained as a pale yellow solid (32.95g, 95%): R_f= 0.6 in 10% MeOH/CH₂Cl₂. ¹H-NMR (CD₃OD, 299.96 MHz): δ (ppm) 6.96-6.93 (d, 2H), 6.69-6.65 (d, 2H), 3.20-3.13 (q, 2H), 2.63-2.58 (t, 2H), 1.41 (s, 9H).

Step 2

[0094] 4-(N-Boc-2-aminoethyl)aniline 28 (1.25 g, 5.29 mmole) was dissolved in methanol (30 mL), followed by addition of phenyl glyoxal 24 (0.708 g, 5.28 mmole). The reaction mixture was stirred for 1 h at rt, prior to addition of NaCNBH₃ (0.665 g, 10.6 mmole). The final mixture was stirred for 12 h at rt, concentrated, and purified by flash silica column chromatography (2 to 5% MeOH/CH₂Cl₂) to give N-(2-phenyl-2-hydroxyethyl)-4-(N-Boc-2-aminoethyl)-aniline as a pale yellow oil (1.71 g, 91%): R_f=0.18 in 5% MeOH/CH₂Cl₂. ¹H-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.4-7.25 (m, 5H), 7.0-6.95 (d, 2H), 6.63-6.60 (d, 2H), 4.85-4.79 (dd, 1H), 3.3-3.21 (t, 2H), 3.2-3.15 (m, 2H), 2.64-2.5 (t, 2H), 1.42 (s, 9H).

Step 3

[0095] A solution of N-(2-phenyl-2-hydroxyethyl)-4-(N-Boc-2-aminoethyl)aniline (1.7 g, 4.77 mmole) in methylene chloride (10 mL) was cooled in ice bath, and TFA (10 mL) was slowly added under a stream of nitrogen gas. The reaction mixture was stirred for 1 h, and concentrated to yield a pale yellow oil. The crude material was purified by reversed phase HPLC (10% to 40% MeCN/H₂O over 50 min; 20 mL/min) to give N-(2-phenyl-2-hydroxyethyl)-4-(2-aminoethyl)aniline 29 as the TFA salt (1.1 g). ¹H-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.42-7.3 (m, 5H), 7.29-7.25 (d, 2H), 7.12-7.0 (d, 2H), 4.85-4.82 (m, 1H), 3.45-3.35 (m, 2H), 3.18-3.1 (t, 2H), 2.98-2.94 (t, 2H); ESMS (C₁₆H₂₀N₂O₁): calcd. 256.4, obsd. 257.1 [M+H]⁺, 278.8 [M+Na]⁺, 513.4 [2M+H]⁺.

Step 4

[0096] To a solution of N-(2-phenyl-2-hydroxyethyl)-4-(2-aminoethyl)aniline trifluoroacetate salt 29 (1.1 g, 2.3 mmole) in methanol (10 mL) was added 5 M NaOH solution (0.93 mL). After stirring for 10 min., the solution was concentrated to dryness. The residue was dissolved in THF (25 mL), and α,α-dihydroxy-4-hydroxy-3-methoxy-carbonylacetophenone 12 (0.514 g, 2.27 mmole) was added. The reaction mixture was stirred for 12 h at rt, cooled to 0 °C, and BH₃/Me₂S (1.14 mL, 10 M) was added under nitrogen atmosphere. The reaction mixture was gradually warmed to rt, stirred for 2 h at rt, and refluxed for 4 h. The reaction mixture was cooled and methanol (10 mL) was added slowly. After stirring for 30 min., at rt, the reaction mixture was concentrated to afford a solid residue, which was dissolved in MeOH (20 mL) containing 10% TFA. Evaporation of the organics yielded a pale yellow oil which was purified by reversed phase HPLC: 10% to 30% MeCN/H₂O over 50 min; 20 mL/min to give 1-{2-[N-2-(4-hydroxy-3-hydroxy-methylphenyl)-2-hydroxyethyl]-amino]ethyl}-4-[N-(2-phenyl-2-hydroxyethyl)-amino]benzene 30 as the TFA salt (0.65 g). ¹H-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.42-7.3 (m, 6H), 7.28-7.24 (d, 2H), 7.18-7.14 (dd, 1H), 7.1-7.07 (d, 2H), 6.80-6.77 (d, 1H), 4.86-4.82 (m, 2H), 4.65 (s, 2H), 3.44-3.34 (m, 2H), 3.28-3.22 (m, 2H), 3.20-3.14 (m, 2H), 3.04-2.96 (m, 2H); ESMS (C₂₅H₃₀N₂O₄): calcd. 422.5, obsd. 423.1 [M+H]⁺, 404.7 [M-1H₂O]⁺, 387.1 [M-2H₂O]⁺.

Example 4

Synthesis of 1-{2-[N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]aminoethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)amino]benzene (following figure 4)

[0097] 

Step 1

[0098] A solution of 4-(N-Boc-2-aminoethyl)aniline 28 (7.0 g, 29.6 mmole) in ethanol (100 mL) and (R)-styreneoxide (3.56 g, 29.6 mmole) was refluxed for 24 h. The organics were removed to give a pale yellow solid. N-(2-phenyl-2-(S)-hydroxyethyl)-4-(N-Boc-2-aminoethyl)aniline was separated by flash silica column chromatography: 1/2 EtOAc/hexane to 3/1 EtOAc/hexane to 3% MeOH in 3/1 EtOAc/hexane: Rf = 0.39 in 3% MeOH/CH₂Cl₂.

Step 2

[0099] A solution of N-(2-phenyl-2-(S)-hydroxyethyl)-4-(N-Boc-2-aminoethyl)-aniline (2.5 g, 7.0 mmole) in CH₂Cl₂ (15 mL) was cooled in an ice bath under stream of nitrogen and TFA (15 mL) was slowly added. The reaction mixture was stirred for 2 h at 0°C and then concentrated in vacuo. The crude product was dissolved in 20% MeCN/H₂O and purified by preparative reversed phase HPLC (5 to 2% MeCN/H₂O over 50 min; 254 nm; 20 mL/min.), to give N-(2-phenyl-2-(S)-hydroxyethyl)-4-(2-aminoethyl)aniline trifluoroacetate salt 31 as a colorless oil. ¹H-NMR (CD₃OD, 299.96 MHz): δ (ppm); 7.45-7.25 (m, 9H), 4.9 (dd, 1H), 3.55-3.45 (m, 2H), 3.21-3.15 (t, 2H), 3.05-2.95 (t, 2H) ESMS (C₁₆H₂₀N₂O₁): calcd. 256.4, obsd. 257.1 [M+H]⁺, 280.2 [M+Na]⁺.

Step 3

[0100] To a solution of N-(2-phenyl-2-(S)-hydroxyethyl)-4-(2-aminoethyl)aniline trifluoroacetate 31 (0.144 g, 0.3 mmole) in methanol (10 mL) was added aq. NaOH solution (1.0 M, 0.625 mL). The solution was concentrated to dryness and the residue was dissolved in anhydrous THF (5 mL). α,α-Dihydroxy-4-hydroxy-3-methoxycarbonylacetophenone 12 (0.067 g, 0.3 mmole) was added and the reaction mixture was stirred for 12 h at rt. BH₃-Me₂S (0.2 mL, 2M) was added at 0°C and the reaction mixture was heated at 75 °C for 6 h. After cooling the reaction mixture in ice bath, MeOH (5 mL) was slowly added to it to quench the reaction, and the reaction mixture was stirred for 30 min., at rt. The organics were removed and the residue was dissolved in TFA/MeOH (1/9; 20 mL), and concentrated. The crude product was dissolved in 20% MeCN/H₂O, and purified by preparative HPLC: 5 to 20% MeCN/H₂O; 20 mL/min; 254 nm.) to give 1-{2-[N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)-amino]benzene 33.

[0101] ¹H-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.42-7.29 (m, 8H), 7.22-7.18 (d, 2H), 7.17-7.14 (dd, 1H), 6.80-6.77 (d, 1H), 4.9-4.85 (m, 2H), 4.65 (s, 2H), 3.5-3.34 (m, 2H), 3.28-3.25 (m, 2H), 3.19-3.14 (m, 2H), 3.04-2.98 (m, 2H); ESMS (C₂₅H₃₀N₂O₄): calcd. 422.5, obsd. 423.1 [M+H]⁺, 446.1 [M+Na]⁺.

[0102] Proceeding as described in Example 4 above but substituting (R)-styreneoxide with (S)-styreneoxide gave 1-{2-[N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-(R)-hydroxyethyl)amino]benzene 34.

[0103] ¹H-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.42-7.28 (m, 8H), 7.20-7.1 (m, 3H), 6.80-6.77 (d, 1H), 4.9-4.85 (m, 2H), 4.65 (s, 2H), 3.45-3.34 (m, 2H), 3.28-3.25 (m, 2H), 3.19-3.15 (m, 2H), 3.04-2.98 (m, 2H); ESMS (C₂₅H₃₀N₂O₄): calcd. 422.5, obsd. 423.1 [M+H]⁺, 446.1 [M+Na]⁺.

Example 5

Synthesis of 1-{2-[N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-(R)-hydroxyethyl]aminoethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)amino]phenyl (following figure 5)

[0104] 

Step 1

[0105] A mixture of 4-(N-Boc-2-aminoethyl)aniline 28 (10 g, 42.34 mmole), benzaldehyde (4.52 mL, 44.47 mmole), and molecular sieves 4A (10 g) in toluene (100 mL) was refluxed at 95 °C for 15 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a colorless oil. The oil was dissolved in MeOH (150 mL) and AcOH (0.5 mL) and NaCNBH₃ (2.79 g, 44.4 mmole) were added. The reaction mixture was stirred at 0°C for 1 h and at rt for 2 h and then concentrated in vacuo to give a pale yellow oily residue. Purification by flash silica column chromatography: 1/1 hexane/EtOAc gave N-benzyl-4-(N-Boc-2-aminoethyl)aniline 41 as colorless oil (11.5 g, 83%). R_f=0.75 in 1/1 hexane/EtOAc. H¹-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.38-7.2 (m, 5H), 6.87-6.84 (d, 2H), 6.58-6.55 (d, 2H), 4.27 (s, 2H), 3.2-3.15 (m, 2H), 2.6-2.56 (t, 2H), 1.41 (s, 9H); ESMS (C₂₀H₂₆N₂O₂): calcd. 326.4, obsd. 328 [M+H]⁺.

Step 2

[0106] A mixture of N-benzyl-4-(N-Boc-2-aminoethyl)aniline 41 (10 g, 30.7 mmole) and (R)-styreneoxide (3.51 mL, 30.7 mmole) in EtOH (100 mL) was refluxed for 48 h. A small aliquot of the reaction mixture was taken out for liquid chromatographic analysis, which indicated that the desired adduct 2-[(N-benzyl-4-[2-N-Boc-aminoethyl)anilino]-1-phenylethanol was formed as a minor product along with another regio-isomer 2-[(N-benzyl-4-[2-N-Boc-aminoethyl)anilino]-2-phenyl-ethanol in a ratio of ~1/2. Evaporation of the solution afforded thick, pale yellow oil, which was purified by flash silica column chromatography: 4/1 to 2/1 hexane/EtOAc. After repeated chromatography, 2-[(N-benzyl-4-[2-N-Boc-aminoethyl)anilino]-1-phenyl-ethanol was obtained as a colorless oil (4.01 g, 29%) (R_f= 0.76 in 2/1 hexane/EtOAc). H¹-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.4-7.1 (m, 10H), 7.1-7.06 (d, 2H), 6.68-6.65 (d, 2H), 5.0 (t, 1H), 4.52-4.46 (d, 1H), 4.26-4.22 (d, 1H), 3.76-3.68 (dd, 1H), 3.56-3.48 (dd, 1H), 3.22-3.12 (m, 2H), 2.68-2.56 (m, 2H), 1.41 (s, 9H); ESMS (C₂₈H₃₄N₂O₃): calcd. 446.6, obsd. 447.1 [M+H]⁺, 893.4 [2M+H]⁺.

Step 3

[0107] To a solution of 2-[(N-benzyl-4-[2-N-Boc-aminoethyl)anilino]-1-phenyl-ethanol (4.01 g, 8.99 mmole) in CH₂Cl₂ (15 mL) maintained in an ice bath was added TFA (15 mL) under stream of nitrogen atmosphere. After stirring at 0 °C for 30 min., the reaction mixture was concentrated in vacuo, yielding a pale yellow oil. Purification by flash silica column chromatography: (½ hexane/EtOAc to 5% i-PrNH₂ in ½ hexane/EtOAc) gave 2-[(N-benzyl-4-[2-aminoethyl)anilino]-1-phenyl-ethanol 42 as a pale yellow oil from such fractions with R_f of 0.2 (5% i-PrNH₂ in ½ hexane/EtOAc) in 74% yield (2.29 g). H¹-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.38-7.06 (m, 10H), 7.01-6.98 (d, 2H), 6.71-6.68 (d, 2H), 5.02-4.96 (dd, 1H), 4.54-4.48 (d, 1H), 4.29-4.23 (d, 1H), 3.76-3.67 (dd, 1H), 3.58-3.50 (dd, 1H), 2.82-2.74 (t, 2H), 2.64-2.59 (t, 2H); ESMS (C₂₃H₂₆N₂O₁): calcd. 346.5, obsd. 346.3[M]⁺,

Step 4

[0108] A mixture of 2-[(N-benzyl-4-[2-aminoethyl)anilino]-1-phenylethanol 42 (2.28 g, 6.59 mmole), benzaldehyde (0.74 mL, 7.28 mmole), and molecular sieves 4A (4 g) in toluene (40 mL) was heated at 90 °C for 14 h. The reaction mixture was cooled and filtered, and the sieves were rinsed with toluene. The combined filtrates were concentrated to give an oily residue which was washed with hexane, and dried. The residue was dissolved in MeOH (40 mL) containing AcOH (0.4 mL) and the reaction mixture was cooled in an ice bath. NaCNBH₃ (0.62 g, 9.87 mmole) was added and the reaction mixture was stirred for 2 h at rt, and then concentrated. The oily residue was dissolved in 60% MeCN/H₂O, and purified by reversed phase preparative liquid chromatography (40 to 80% MeCN/H₂O over 30 min; 30 mL/min) to give 2-[(N-benzyl-4-[2-N-benzylaminoethyl)anilino]-1-phenylethanol as the TFA salt. The product was treated with alkaline brine solution, and extracted with ether (200 mL). The organic layer was dried with NaSO₄, and concentrated, to give 2-[(N-benzyl-4-[2-N-benzylaminoethyl)anilino]-1-phenylethanol 43 as a colorless oil (1.36 g). H¹-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.36-7.06 (m, 15H), 6.98-6.95 (d, 2H), 6.69-6.60 (d, 2H), 5.01-4.96 (t, 1H), 4.54-4.47 (d, 1H), 4.29-4.24 (d, 1H), 3.73 (s, 2H), 3.72-3.68 (dd, 1H), 3.59-3.54 (dd, 1H), 2.80-2.74 (m, 2H), 2.70-2.64 (m, 2H); ESMS (C₃₀H₃₂N₂O₁): calcd. 436.6, obsd. 437.2 [M+H]⁺.

Step 5

[0109] A concentrated solution of 2-[(N-benzyl-4-[2-N-benzylaminoethyl)anilino]-1-phenylethanol (1.36 g, 3.12 mmole) and compound (S)-4-benzyloxy-3-methoxycarbonylstyreneoxide 44 (0.887 g, 3.12 mmole; ~95% ee) (prepared as described in R. Hett, R. Stare, P. Helquist, Tet. Lett., 35, 9375-9378, (1994)) in toluene (1 mL) was heated at 105 °C for 72 h under nitrogen atmosphere. The reaction mixture was purified by flash silica column chromatography (2/1 hexane/EtOAc to 3% MeOH in 1/1 hexane/EtOAc) to give 1-{2-[N-benzyl-N-2-(4-benzyloxy-3-methoxycarbonylphenyl)-2-(R)-hydroxy]ethylaminoethyl}-4-[N-(2-phenyl-2-(S)-hydroxy)ethylamino]benzene 45. (R_f= 0.62 in 3% MeOH in 1/1 hexane/EtOAc) was obtained as a pale yellow foam (2.0 g, 89%).

[0110] H¹-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.67-7.66 (d, 1H), 7.49-7.42 (m, 2H), 7.38-7.0 (m, 20H), 6.88-6.85 (d, 2% 6.65-6.62 (d, 2H), 5.15 (s, 2H), 5.05-4.98 (t, 1H), 4.6-4.54 (t, 1H), 4.53-4.46 (d, 1H), 4.28-4.22 (d, 1H), 3.84 (s, 3H), 3.72-3.64 (m, 3H), 3.56-3.46 (dd, 1H), 2.74-2.56 (m, 6H); ESMS (C₄₇H₄₈N₂O₅): calcd. 720.9, obsd. 721.4 [M+H]⁺, 743.3 [M+Na]⁺.

Step 6

[0111] To a suspension of LiAlH₄ (0.21 g, 5.56 mmole) in THF (40 mL) cooled with ice bath was added 1-{2-[N-benzyl-N-2-(4-benzyloxy-3-methoxycarbonylphenyl)-2-(R)-hydroxyethyl]aminoethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)amino]benzene 45 (2.0 g, 2.78 mmole) in THF (10 mL) under nitrogen atmosphere. The reaction mixture was warmed slowly to rt and the stirring was continued for 5 h. The reaction was cooled to 0°C, and 10% NaOH (0.5 mL) was slowly added. After 30 min., a thick gel formed. The gel was diluted with THF (300 mL), filtered, and the solid mass was rinsed with THF (50 mL). The filtrates were combined, and concentrated in vacuo, yielding an oily residue.

[0112] The residue was purified by flash silica column chromatography (2/1 hexane/EtOAc to 3% MeOH in 1/1 hexane/EtOAc) to give 1-{2-[N-benzyl-N-2-(4-benzyloxy-3-hydroxymethylphenyl)-2-(R)-hydroxyethyl]aminoethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)amino]benzene as a colorless oil (1.28 g, 67%). H¹-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.4-7.0 (m, 22H), 6.85-6.82 (m, 3H), 6.63-6.60 (d, 2H), 5.02-4.94 (m, 3H), 4.66 (s, 2H), 4.59-4.54 (dd, 1H), 4.48-4.4 (d, 1H), 4.24-4.16 (d, 1H), 3.76-3.7 (d, 1H), 3.69-3.62 (dd, 1H), 3.58-3.52 (d, 1H), 3.50-3.44 (dd, 1H), 2.76-2.54 (m, 6H); ESMS (C₄₆H₄₈N₂O₄): calcd. 692.90, obsd. 693.5 [M+H]⁺.

Step 7

[0113] A solution of 1-{2-[N-benzyl-N-2-(4-benzyloxy-3-hydroxymethylphenyl)-2-(R)-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)amino]-benzene (1.28 g, 1.85 mmole) in EtOH (80 mL) was hydrogenated under H₂ (1 atm) with 10% Pd/C (0.6 g) for 36 h. After filtration and rinsing of the catalyst with EtOH (50 mL), the filtrates were combined, and evaporated in vacuo, yielding pale yellow foam which was dissolved in 10% MeCN/H₂O, and purified by reversed phase preparative liquid chromatography (10 to 30% MeCN/H₂O (containing 0.3% TFA) over 50 min; 30 mL/min; 254 nm) to give 1-{2-[N-2-(4-hydroxy-3-hydroxymethyl-phenyl)-2-(R)-hydroxyethyl]aminoethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)-amino]benzene as the TFA salt (0.6 g, 50%). Optical purity of 1-{2-[N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-(R)-hydroxyethyl]aminoethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)amino]benzene 46 which was analyzed with capillary electrophoresis by using a chiral medium, and estimated to be ~93%.

[0114] H¹-NMR (CD₃OD, 299.96 MHz): δ (ppm) 7.42-7.28 (m, 8H), 7.26-7.22 (d, 2H), 7.18-7.14 (dd, 1H), 6.80-6.77 (d, 1H), 4.88-4.82 (m, 2H), 4.65 (s, 2H), 3.5-3.43 (m, 2H), 3.29-3.26 (m, 2H), 3.19-4.14 (m, 2H), 3.06-3.0 (m, 2H); ESMS (C₂₅H₃₀N₂O₄): calcd. 422.5, obsd. 423.1 [M+H]⁺, 445.4 [M+Na]⁺,

Example 6

Synthesis of 1-{6-[N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-[hydroxyethyl]-amino]hexyloxy}-4-{6-[N-[2-(4-hydroxy-3-hydroxy-methylphenyl)-2-hydroxyethyl]amino]hexyloxypropyl}benzene (following figure 6)

[0115] 

Step 1

[0116] A solution of 3-(4-hydroxyphenyl)-1-propanol (2.0 g, 13.1 mmole) in DMF (5 mL) was added to a solution of DMF (35 mL) containing NaH (1.31 g, 60% in mineral oil) at 0°C under nitrogen atmosphere. The reaction mixture was slowly warmed to 80 °C. After stirring for 1 h at 80 °C, the reaction mixture was cooled to 0 °C, and 6-bromohexanenitrile (5.78 g, 32.83 mmole) was added. The final mixture was re-heated to 80 °C, and stirred for 24 h. The reaction mixture was quenched with saturated NaCl solution (200 mL), and the product was extracted with EtOAc (300 mL). The organic layer was washed with brine solution, dried with Na₂SO₄, and evaporated to dryness, yielding a pale yellow solid. Purification of the crude product by flash silica column chromatography: 4/1 to 1/1 hexane/EtOAc provided 6-{3-[4-(5-cyanopentyloxy)phenyl]propoxy}hexanenitrile in 30% yield (1.33 g). R_f= 0.63 in 1/1 EtOAc/hexane. ¹H-NMR (CDCl₃, 299.96 MHz): δ (ppm) 7.09-7.07 (d, 2H), 6.81-6.78 (d, 2H), 3.96-3.92 (t, 2H), 3.42-3.37 (m, 4H), 2.64-2.58 (t, 2H), 2.39-2.32 (m, 4H), 1.87-1.52 (m, 14 H).

Step 2

[0117] A solution of 6-{3-[4-(5-pentyloxy)phenyl]propoxy}hexanenitrile (1.33 g, 3.88 mmole) in THF (10 mL) was added to a solution of LiAlH₄ (0.442 g, 11.65 mmole) in THF (50 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was heated slowly to reflux, and stirred for 2 h. The reaction mixture was cooled to 0 °C, and 10% NaOH solution (5 mL) was slowly added. After 30 min., the reaction mixture was filtered, and the collected solids were washed with THF (100 mL). The filtrate was concentrated to yield a pale yellow oil which was purified by flash silica column chromatography: 5% MeOH/CH₂Cl₂ to 3% i-PrNH₂/20% MeOH/CH₂Cl₂ to give 6-{3-[4-(6-aminohexyloxy)-phenyl]propoxy}-hexylamine as a colorless oil (0.5 g, 37%) which was converted to the desired compound by proceeding as described in Example 1, step 2 above. The crude product was purified by preparatory reversed phase HPLC: 10 to 40% MeCN/H₂O over 40 min; 20 mL/min; 254 nm. ESMS (C₃₉H₅₈N₂O₈): calcd. 682.8, obsd. 683.6 [M+H]⁺, 797.5 [M+CF₃CO₂H]⁺.

Example 7

Synthesis of 1-{2-[N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-napth-1-yloxymethyl-2-hydroxyethyl)amino]benzene (following figure 7)

[0118] 

Step 1

[0119] A solution of EtOH (50 mL) containing 4-(N-Boc-2-aminoethyl)aniline 28 (0.4 g, 1.69 mmole) and 3-(1-naphthoxy)-1,2-epoxypropane 55 (0.33 g, 1.65 mmole) was refluxed for 18 h, and concentrated in vacuo to dryness, yielding a pale yellow oil. It was dissolved in 10 mL of CH₂Cl₂, cooled in ice bath, and treated with TFA (5 mL). After stirring for 2 h at 0°C, the mixture was evaporated, yielding a pale red oil. It was dissolved in 30% aqueous acetonitrile, and purified by preparatory HPLC: 10 to 30% MeCN/H₂O over 30 min; 20 mL/min; 254 nm. The product 56 was obtained as colorless oil (260 mg; TFA salt). H¹-NMR (CD₃OD, 299.96 MHz): (ppm) 8.88-8.25 (dd, 1H), 7.82-7.79 (dd, 1H), 7.51-7.42 (m, 3H), 7.39-7-38 (d, 1H), 7.33-7.30 (d, 2H), 7.25-7.23 (d, 2H), 6.91-6.89 (d, 1H), 4.37-4.31 (m, 1H), 4.22-4.19 (m, 2H), 3.69-3.63 (dd, 1H), 3.67-3.54 (dd, 1H), 3.17-3.11 (t, 2H), 2.96-2.91 (t, 2H); ESMS (C₂₁H₂₄N₂O₂): calcd. 336.4, obsd. 337.5 [M+H]⁺, 359.6 [M+Na]⁺, 673.4 [2M+H]⁺.

Step 2

[0120] To a solution of compound 56 (0.13 g, 0.023 mmole; TFA salt) in 5 mL of MeOH was added 1.0 M NaOH (1.0 M, 0.46 mL). After homogeneous mixing, the solution was evaporated to dryness. The residue was dissolved in THF (10 mL), followed by addition of glyoxal 12 (52 mg; 0.023 mmole). The resulting suspension was stirred for 4 h at ambient temperature under nitrogen atmosphere. After cooling of the resulting solution in ice bath, an excess amount of 2M BH₃-Me₂S in THF (3 mL; 6 mmole) was added to the previous reaction solution. The resulting mixture was slowly warmed to rt, and refluxed for 4 h under N₂ stream. After cooling of the hot solution, 5 mL of MeOH was added to the cooled mixture to quench the reaction mixture under nitrogen atmosphere. After stirring 30 min at rt, the final solution was evaporated in vacuo, yielding a pale brown solid. It was washed with EtOAc/hexane (1/2; 20 mL), and dried. The crude product was dissolved in 50% MeCN/H₂O containing 0.5% TFA, and purified by prep-scale high performance liquid chromatography (HPLC) using a linear gradient (5% to 50% MeCN/H₂O over 50 min, 20 mL/min; detection at 254 nM). Fractions with UV absorption were analyzed by LC-MS to locate the desired product 1-{2-[N-2-(4-hydroxy-3-hydroxy-methylphenyl)-2-hydroxyethyl]amino]-ethyl}-4-[N-(2-napth-1-yloxymethyl-2-hydroxy-ethyl)amino]benzene 57. ESMS (C₃₀H₃₄N₂O₅): calcd. 502.6, obsd. 503.2 [M+H]⁴, 525.6 [M+Na]⁺.

Formulation Examples

Example 1

[0121] Hard gelatin capsules containing the following ingredients are prepared:

Ingredient	Quantity (mg/capsule)
Active Ingredient	30.0
Starch	305.0
Magnesium stearate	5.0

[0122] The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.

Example 2

[0123] A tablet Formula is prepared using the ingredients below:

Ingredient	Quantity (mg/tablet)
Active Ingredient	25.0
Cellulose, microcrystalline	200.0
Colloidal silicon dioxide	10.0
Stearic acid	5.0

[0124] The components are blended and compressed to form tablets, each weighing 240 mg.

Example 3

[0125] A dry powder inhaler formulation is prepared containing the following components:

Ingredient	Weight %
Active Ingredient	5
Lactose	95

[0126] The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.

Example 4

[0127] Tablets, each containing 30 mg of active ingredient, are prepared as follows:

Ingredient	Quantity (mg/tablet)
Active Ingredient	30.0 mg
Starch	45.0 mg
Microcrystalline cellulose	35.0 mg
Polyvinylpyrrolidone (as 10% solution in sterile water)	4.0 mg
Sodium carboxymethyl starch	4.5 mg
Magnesium stearate	0.5 mg
Talc	1.0 mg
Total

[0128] The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50E to 60EC and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.

Example 5

[0129] Capsules, each containing 40 mg of medicament are made as follows:

Ingredient	Quantity (mg/capsule)
Active Ingredient	40.0 mg
Starch	109.0 mg
Magnesium stearate	1.0 mg
Total

[0130] The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.

Example 6

[0131] Suppositories, each containing 25 mg of active ingredient are made as follows:

Ingredient	Amount
Active Ingredient	25 mg
Saturated fatty acid glycerides to	2,000 mg

[0132] The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

Example 7

[0133] Suspensions, each containing 50 mg of medicament per 5.0 mL dose are made as follows:

Ingredient	Amount
Active Ingredient	50.0 mg
Xanthan gum	4.0 mg
Sodium carboxymethyl cellulose (11%)
Microcrystalline cellulose (89%)	50.0 mg
Sucrose	1.75 g
Sodium benzoate	10.0 mg
Flavor and Color	q.v.
Purified water to	5.0 mL

[0134] The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.

Example 8

[0135] A formulation may be prepared as follows:

Ingredient	Quantity (mg/capsule)
Active Ingredient	15.0 mg
Starch	407.0 mg
Magnesium stearate	3.0 mg
Total

[0136] The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425.0 mg quantities.

Example 9

[0137] A formulation may be prepared as follows:

Ingredient	Quantity
Active Ingredient	5.0 mg
Corn Oil	1.0 mL

Example 10

[0138] A topical formulation may be prepared as follows:

Ingredient	Quantity
Active Ingredient	1-10 g
Emulsifying Wax	30 g
Liquid Paraffin	20 g
White Soft Paraffin	to 100 g

[0139] The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.

[0140] Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference in its entirety. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0141] Other suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

Biological Examples

Example I

β2-Adrenergic Receptor In Vitro Functional Assay

[0142] The β2-adrenergic receptor functional activity of compounds of the invention was tested follows.

Cell Seeding and Growth:

[0143] Primary bronchial smooth muscle cells from a 21 yr. old male (Clonetics, San Diego, CA) were seeded at 50,000 cells/well in 24-well tissue culture plates. The media used was Clonetic's SmBM-2 supplemented with hEGF, Insulin, hFGF, and Fetal Bovine Serum. Cells were grown two days at 37°C, 5% CO₂ until confluent monolayers were seen.

Agonist Stimulation of Cells

[0144] The media was aspirated from each well and replaced with 250 ml fresh media containing 1mM IBMX, a phospodiesterase inhibitor (Sigma, St Louis, MO). Cells were incubated for 15 minutes at 37 °C, and then 250 ml of agonist at appropriate concentration was added. Cells were then incubated for an additional 10 minutes. Media was aspirated and 500 ml cold 70% EtOH was added to cells, and then removed to an empty 96-well deep-well plate after about 5 minutes. This step was then repeated. The deep-well plate was then spun in a speed-vac until all EtOH dried off, leaving dry pellets. cAMP (pmol/well) was quantitated using a cAMP ELISA kit from Stratagene (La Jolla, CA). EC₅₀ curves were generated using the 4-parameter fit equation:

where,
   y = cpm   a = total binding   c = IC₅₀
   x = [compound]   d = NS binding   b = slope
   Fix NS binding and allow all other parameters to float.

Example 2

β2-Adrenergic Receptor In Vitro Radioligand Binding Assay

[0145] The β1/2-adrenergic receptor binding activity of compounds of the invention can be tested follows. SF9 cell membranes containing either β1 or β2-adrenergic receptor (NEN, Boston, MA) were incubated with 0.07 nM ¹²⁵I-iodocyanopindolol (NEN, Boston, MA) in binding buffer containing 75mM Tris-HCl (pH 7.4), 12.5 mM MgCl₂ and 2 mM EDTA and varying concentrations of test compounds or buffer only (control) in 96-well plates. The plates were incubated at room temperature with shaking for 1 hour. The receptor bound radioligand was harvested by filtration over 96-well GF/B filter plates (Packard, Meriden, CT) pre-blocked with 0.3%polyethylenimine and washed twice with 200Φ1 PBS using cell harvester. The filters were washed thrice with 200Φ1 PBS using cell harvester and then resuspended in 40Φ1 scintillation cocktail. The filter-bound radioactivity was measured with a scintillation counter and IC₅₀ curves are generated using the standard 4-parameter fit equation described above.

Claims

1. A bivalent multibinding compound of Formula (II) or a pharmaceutically acceptable salt thereof:

wherein:

Ar¹ is a phenyl ring of formula (c):

wherein:

R⁴ is hydrogen, alkyl, halo, or alkoxy;

R⁵ is hydrogen, hydroxy, halo or amino;

R⁶ is hydrogen, halo, hydroxy, alkoxy, substituted alkyl, or -NRC(O)R wherein each R is hydrogen or alkyl; or Ar¹ is 2,8-dihydroxyquinolin-5-yl;

Ar³ is either:

(i) a phenyl ring of formula (c) as defined above; or

(ii) a phenyl ring of formula (d):

wherein:

R⁷ is hydrogen, alkyl, alkenyl, substituted alkyl, halo, alkoxy, substituted alkoxy or hydroxy; and

R⁸ is hydrogen, halo, alkoxy or substituted alkoxy; or

(iii) naphthyl;

where substituted alkyl means hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl, 2-sulfonamidoethyl or 2-carboxyethyl, and substituted alkoxy means (substituted alkyl)-O-;
   W is a bond, or an alkylene chain wherein one or more of the carbon atoms in the alkylene group are optionally replaced by -O-;
   Ar² is phenylene wherein the W and the X groups are attached at the 1,2-, 1,3, and 1,4 positions of the phenyl ring; or cyclohexylene optionally substituted with methyl and wherein the W and the X groups are attached at the 1,3, and 1,4 positions of the cyclohexyl ring;
   X is a covalent bond; and
   Q is -NH-CH₂ -CH(OH)-; -NH-CH(CH₂OH)-; -(CH₂)₃-O-(CH₂)₆-NH-CH₂-CH(OH)-; or -NH-CH₂-CH(OH)-CH₂-O-.

2. A compound as claimed in claim 1, wherein in Ar¹
   R⁴ is selected from the group consisting of hydrogen, methyl, fluoro, chloro and methoxy;
   R⁵ is selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, and amino; and
   R⁶ is selected from the group consisting of hydrogen, chloro, fluoro, hydroxy, methoxy, hydroxymethyl and -NHCHO.

3. A compound as claimed in claim 1, wherein Ar¹ is 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3-(HCONH-)phenyl, 3,5-dichloro-4-aminophenyl, or 2,8-dihydroxyquinolin-5-yl.

4. A compound as claimed in claim 3, in which Ar¹ is 2,8-dihydroxyquinolin-5-yl.

5. A compound as claimed in any one of claims 1 to 4, wherein Ar³ is

(i) a phenyl ring of formula (c), wherein
   R⁴ is selected from the group consisting of hydrogen, methyl, fluoro, chloro and methoxy;
   R⁵ is selected from the group consisting of hydrogen, hydroxy, fluoro, chloro and amino; and
   R⁶ is selected from the group consisting of hydrogen, chloro, fluoro, hydroxy, methoxy, hydroxymethyl and -NHCHO; or

(ii) a phenyl ring of formula (d), wherein
   R⁷ is selected from the group consisting of hydrogen, methyl, propen-2-yl, fluoro, chloro, methoxy and hydroxy; and
   R⁸ is selected from the group consisting of hydrogen, fluoro, chloro and methoxy.

6. A compound as claimed in any one of claims 1 to 4, wherein Ar³ is selected from the group consisting of:

7. A compound as claimed in claim 1, wherein Ar³ has the meaning given in claim 4, and wherein Ar¹ is selected from the group consisting of phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-dichlorophenyl, 2-chloro-3,4-dihydroxyphenyl, 2-fluoro-3,4-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3-(HCONH-)phenyl, 3-chlorophenyl, 2,5-dimethoxyphenyl, 3,5-dichloro-4-aminophenyl, and 2,8-dihydroxyquinolin-5-yl.

8. A compound as claimed in any one of claims 1 to 7 in which Ar² is 1,4-phenylene.

9. A compound as claimed in any one of claims 1 to 8, in which W is a bond, methylene, ethylene, propylene, -(CH₂)₆-O-(CH₂)₃- or -(CH₂)₆-O-.

10. A compound as claimed in Claim 9, wherein Ar³ is phenyl or 4-hydroxy-3-hydroxymethylphenyl.

11. A compound having the formula:

   wherein the stereochemistry at *C and at **C is selected from the group consisting of (RS) and (RS); (RS) and (R); (RS) and (S); (R) and (S); and (R) and (R);
   and pharmaceutically acceptable salts thereof.

12. A compound as claimed in claim 11 wherein the stereochemistry at *C and at **C is (R) and (R).

13. A compound as claimed in claim 1, which is one of the following compounds: trans-1,4-bis{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}cyclohexane; 1,8-bis{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}-p-menthane; 1-{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]aminomethyl}-2-N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}benzene; 1-{2-[N-2-[(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}benzene; 1-{N-[2-(4-hydroxy-3-hydroxy-methylphenyl)-2-hydroxyethyl]aminomethyl}-4-{N-[2-(4-hydroxy-3-hydroxy-methylphenyl)-2-hydroxyethyl]amino}benzene; 1-{2-[N-2-[(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}-ethyl}-4-{N-[2-phenyl-2-hydroxyethyl]amino}benzene; 1-{2-[N-[2-phenyl-2-hydroxyethyl)aminoethyl}-4-[N-(2-phenyl-2-hydroxyethyl)amino]-benzene; 1-{2-[N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)-amino]benzene; 1-{2-[N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-(R)-hydroxyethyl)amino]benzene; 1-{2-{N-2-(4-hydroxy-3-hydroxymethylphenyl)-2-(R)-hydroxyethyl]aminoethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)amino]benzene; 1-{2-[N-2-(4-hydroxy-3-hydroxy-methylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-napth-1-yloxymethyl-2-hydroxyethyl)amino]benzene; or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound as claimed in any one of claims 1 to 13.

15. A compound as claimed in any one of claims 1 to 13 or a pharmaceutical composition as claimed in claim 14, for use as a medicament, especially a medicament for treating a disease mediated by a β₂ adrenergic receptor in a mammal.

16. Use of a compound as claimed in any one of claims 1 to 13 or a pharmaceutical composition as claimed in claim 14, in the manufacture of a medicament for treating a disease mediated by a β2 adrenergic receptor in a mammal.

17. A compound or a composition as claimed in claim 15 or use as claimed in claim 16, wherein the medicament is for the treatment of a respiratory disease, especially asthma.

Ansprüche

1. Eine bivalente mehrfachbindende Verbindung der Formel (II) oder ein pharmazeutisch annehmbares Salz davon:

wobei:

Ar¹ ein Phenylring der Formel (c) ist:

wobei:

R⁴ Wasserstoff, Alkyl, Halogen oder Alkoxy ist,

R⁵ Wasserstoff, Hydroxy, Halogen oder Amino ist,

R⁶ Wasserstoff, Halogen, Hydroxy, Alkoxy, substituiertes Alkyl oder -NRC(O)R ist, wobei jedes R Wasserstoff oder Alkyl ist, oder wobei Ar¹ 2,8-Dihydroxychinolin-5-yl ist,

Ar³ entweder

(i) ein Phenylring der wie oben definierten Formel (c) oder

(ii) ein Phenylring der Formel (d):

wobei:

R⁷ Wasserstoff, Alkyl, Alkenyl, substituiertes Alkyl, Halogen, Alkoxy, substituiertes Alkoxy oder Hydroxy ist und

R⁸ Wasserstoff, Halogen, Alkoxy oder substituiertes Alkoxy ist, oder

(iii) Naphthyl ist,

wobei substituiertes Alkyl Hydroxymethyl, Hydroxyethyl, Hydroxypropyl, 2-Aminoethyl, 3-Aminopropyl, 2-Methylaminoethyl, 3-Dimethylaminopropyl, 2-Sulfonamidoethyl oder 2-Carboxyethyl bedeutet und substituiertes Alkoxy (substituiertes Alkyl)-O-bedeutet,
   W eine Bindung oder eine Alkylenkette ist, wobei eines oder mehrere der Kohlenstoffatome in der Alkylengruppe gegebenenfalls durch -O- ersetzt sind,
   Ar² Phenylen, wobei die W- und die X-Gruppen an die 1,2-, 1,3- und 1,4-Positionen des Phenylrings gebunden sind, oder Cyclohexylen, gegebenenfalls mit Methyl substituiert und wobei die W- und die X-Gruppen an die 1,3- und 1,4-Positionen des Cyclohexylrings gebunden sind, ist,
   X eine kovalente Bindung ist und
   Q -NH-CH₂-CH(OH)-, -NH-CH(CH₂OH)-, -(CH₂)₃-O-(CH₂)₆-NH-CH₂-CH(OH)- oder -NH-CH₂-CH(OH)-CH₂-O- ist.

2. Eine wie in Anspruch 1 beanspruchte Verbindung, wobei bei Ar¹
   R⁴ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Methyl, Fluor, Chlor und Methoxy,
   R⁵ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Hydroxy, Fluor, Chlor und Amino, und
   R⁶ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Chlor, Fluor, Hydroxy, Methoxy, Hydroxymethyl und -NHCHO.

3. Eine wie in Anspruch 1 beanspruchte Verbindung, wobei Ar¹ 4-Hydroxy-3-hydroxymethylphenyl, 4-Hydroxy-3-(HCONH-)phenyl, 3,5-Dichlor-4-aminophenyl oder 2,8-Dihydroxychinolin-5-yl ist.

4. Eine wie in Anspruch 3 beanspruchte Verbindung, wobei Ar¹ 2,8-Dihydroxychinolin-5-yl ist.

5. Eine wie in irgendeinem der Ansprüche 1 bis 4 beanspruchte Verbindung, wobei Ar³

(i) ein Phenylring der Formel (c), wobei
   R⁴ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Methyl, Fluor, Chlor und Methoxy,
   R⁵ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Hydroxy, Fluor, Chlor und Amino, und
   R⁶ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Chlor, Fluor, Hydroxy, Methoxy, Hydroxymethyl und -NHCHO, oder

(ii) ein Phenylring der Formel (d) ist, wobei
   R⁷ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Methyl, Propen-2-yl, Fluor, Chlor, Methoxy und Hydroxy, und
   R⁸ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Fluor, Chlor und Methoxy.

6. Eine wie in irgendeinem der Ansprüche 1 bis 4 beanspruchte Verbindung, wobei Ar³ ausgewählt ist aus der Gruppe, bestehend aus:

7. Eine wie in Anspruch 1 beanspruchte Verbindung, wobei Ar³ die in Anspruch 6 angegebene Bedeutung besitzt und Ar¹ ausgewählt ist aus der Gruppe, bestehend aus Phenyl, 4-Hydroxyphenyl, 3,4-Dihydroxyphenyl, 3,4-Dichlorphenyl, 2-Chlor-3,4-dihydroxyphenyl, 2-Fluor-3,4-dihydroxyphenyl, 4-Hydroxy-3-methoxyphenyl, 4-Hydroxy-3-hydroxymethylphenyl, 4-Hydroxy-3-(HCONH-)phenyl, 3-Chlorphenyl, 2,5-Dimethoxyphenyl, 3,5-Dichlor-4-aminophenyl und 2,8-Dihydroxychinolin-5-yl.

8. Eine wie in irgendeinem der Ansprüche 1 bis 7 beanspruchte Verbindung, wobei Ar² 1,4-Phenylen ist.

9. Eine wie in irgendeinem der Ansprüche 1 bis 8 beanspruchte Verbindung, wobei W eine Bindung, Methylen, Ethylen, Propylen, -(CH₂)₆-O-(CH₂)₃- oder -(CH₂)₆-O- ist.

10. Eine wie in Anspruch 9 beanspruchte Verbindung, wobei Ar³ Phenyl oder 4-Hydroxy-3-hydroxymethylphenyl ist.

11. Eine Verbindung mit der Formel:

wobei die Stereochemie an *C und an **C ausgewählt ist aus der Gruppe, bestehend aus (RS) und (RS), (RS) und (R), (RS) und (S), (R) und (S), und (R) und (R),
   und pharmazeutisch annehmbare Salze davon.

12. Eine wie in Anspruch 11 beanspruchte Verbindung, wobei die Stereochemie an *C und an **C (R) und (R) ist.

13. Eine wie in Anspruch 1 beanspruchte Verbindung, die eine der folgenden Verbindungen ist: trans-1,4-Bis{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}cyclohexan, 1,8-Bis{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]-amino}-p-menthan, 1-{N-[2-(4-Hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]aminomethyl}-2-N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}benzol, 1-{2-[N-2-[(4-Hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}benzol, 1-{N-[2-(4-Hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]aminomethyl}-4-{N-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}benzol, 1-{2-[N-2-[(4-Hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino}ethyl}-4-{N-[2-phenyl-2-hydroxyethyl]amino]benzol, 1-{2-[N-[2-Phenyl-2-hydroxyethyl]aminoethyl}-4-[N-(2-phenyl-2-hydroxyethyl)amino]benzol, 1-{2-[N-2-(4-Hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)amino]benzol, 1-{2-[N-2-(4-Hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-(R)-hydroxyethyl)-amino]benzol, 1-{2-{N-2-(4-Hydroxy-3-hydroxymethylphenyl)-2-(R)-hydroxyethyl]aminoethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)-amino]benzol, 1-{2-[N-2-(4-Hydroxy-3-hydroxymethylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-naphth-1-yloxymethyl-2-hydroxyethyl)amino]benzol, oder ein pharmazeutisch annehmbares Salz davon.

14. Eine pharmazeutische Zusammensetzung, die einen pharmazeutisch annehmbaren Träger und eine wirksame Menge einer wie in irgendeinem der Ansprüche 1 bis 13 beanspruchten Verbindung enthält.

15. Eine wie in irgendeinem der Ansprüche 1 bis 13 beanspruchte Verbindung oder eine wie in Anspruch 14 beanspruchte pharmazeutische Zusammensetzung zur Verwendung als ein Medikament, insbesondere als ein Medikament zur Behandlung einer durch einen β₂-adrenergen Rezeptor vermittelten Erkrankung bei einem Säugetier.

16. Die Verwendung einer wie in irgendeinem der Ansprüche 1 bis 13 beanspruchten Verbindung oder einer wie in Anspruch 14 beanspruchten pharmazeutischen Zusammensetzung zur Herstellung eines Medikaments zur Behandlung einer durch einen β₂-adrenergen Rezeptor vermittelten Erkrankung bei einem Säugetier.

17. Eine wie in Anspruch 15 beanspruchte Verbindung oder Zusammensetzung oder eine wie in Anspruch 16 beanspruchte Verwendung, wobei das Medikament zur Behandlung einer Atemwegserkrankung, insbesondere Asthma, dient.

Revendications

1. Composé multiliaison bivalent selon la formule (II) ou sel pharmaceutiquement acceptable de celui-ci:

   où:

Ar¹ représente un noyau phényle répondant à la formule (c):

   dans laquelle:

R⁴ représente un atome d'hydrogène, un groupe alkyle, un groupe halogéno, ou un groupe alcoxy;

R⁵ représente un atome d'hydrogène, un groupe hydroxy, un groupe halogéno, ou un groupe amino;

R⁶ représente un atome d'hydrogène, un groupe halogéno, un groupe hydroxy, un groupe alcoxy, un groupe alkyle substitué, ou -NRC(O)R dans lequel chaque R représente un atome d'hydrogène ou un groupe alkyle; ou Ar¹ représente un groupe 2,8-dihydroxyquinoléin-5-yle;

Ar³ représente soit:

(i) un noyau phényle répondant à la formule (c) tel que défini précédemment; soit

(ii) un noyau phényle répondant à la formule (d):

dans laquelle:

R⁷ représente un atome d'hydrogène, un groupe alkyle, un groupe alcényle, un groupe alkyle substitué, un groupe halogéno, un groupe alcoxy, un groupe alcoxy substitué ou un groupe hydroxy; et

R⁸ représente un atome d'hydrogène, un groupe halogéno, un groupe alcoxy,

ou un groupe alcoxy substitué; ou

(iii) un groupe naphtyle,

   dans lequel un groupe alkyle substitué désigne un groupe hydroxyméthyle, un groupe hydroxyéthyle, un groupe hydroxypropyle, un groupe 2-aminoéthyle, un groupe 3-aminopropyle, un groupe 2-méthylaminoéthyle, un groupe 3-diméthylaminopropyle, un groupe 2-sulfonamidoéthyle ou un groupe 2-carboxyéthyle et un groupe alcoxy substitué désigne un groupe (alkyle substitué)-O-;
   W représente une liaison ou une chaîne alkylène dans laquelle un ou plusieurs des atomes de carbone dans le groupe alkylène sont éventuellement remplacés par-O-;
   Ar² représente un phénylène dans lequel les groupes W et X sont attachés au niveau des positions 1,2-, 1,3 et 1,4 du noyau phényle; ou un cyclohexylène éventuellement substitué par un groupe méthyle et dans lequel les groupes W et X sont attachés au niveau des positions 1,3 et 1,4 du noyau cyclohexyle;
   X représente une liaison covalente; et
   Q représente -NH-CH₂-CH(OH)-; -NH-CH(CH₂OH)-; -(CH₂)₃-O-(CH₂)₆-NH-CH₂-CH(OH)-; ou -NH-CH₂-CH(OH)-CH₂-O-.

2. Composé selon la revendication 1, dans lequel dans Ar¹
   R⁴ est choisi dans le groupe constitué par un atome d'hydrogène, un groupe méthyle, un groupe fluoro, un groupe chloro et un groupe méthoxy;
   R⁵ est choisi dans le groupe constitué par un atome d'hydrogène, un groupe hydroxy, un groupe fluoro, un groupe chloro, et un groupe amino; et
   R⁶ est choisi dans le groupe constitué par un atome d'hydrogène, un groupe chloro, un groupe fluoro, un groupe hydroxy, un groupe méthoxy, un groupe hydroxyméthyle et -NHCHO.

3. Composé selon la revendication 1, dans lequel Ar¹ représente un groupe 4-hydroxy-3-hydroxyméthylphényle, un groupe 4-hydroxy-3-(HCONH-)phényle, un groupe 3,5-dichloro-4-aminophényle, ou un groupe 2,8-dihydroxyquinoléin-5-yle.

4. Composé selon la revendication 3, dans lequel Ar1 représente un groupe 2,8-dihydroxyquinoléin-5-yle.

5. Composé selon l'une quelconque des revendications 1 à 4, dans lequel Ar³ représente

(i) un noyau phényle répondant à la formule (c), dans laquelle
   R⁴ est choisi dans le groupe constitué par un atome d'hydrogène, un groupe méthyle, un groupe fluoro, un groupe chloro et un groupe méthoxy;
   R⁵ est choisi dans le groupe constitué par un atome d'hydrogène, un groupe hydroxy, un groupe fluoro, un groupe chloro et un groupe amino; et
   R⁶ est choisi dans le groupe constitué par un atome d'hydrogène, un groupe chloro, un groupe fluoro, un groupe hydroxy, un groupe méthoxy, un groupe hydroxyméthyle et -NHCHO; ou

(ii) un noyau phényle répondant à la formule (d), dans laquelle
   R⁷ est choisi dans le groupe constitué par un atome d'hydrogène, un groupe méthyle, un groupe propèn-2-yle, un groupe fluoro, un groupe chloro, un groupe méthoxy et un groupe hydroxy; et
   R⁸ est choisi dans le groupe constitué par un atome d'hydrogène, un groupe fluoro, un groupe chloro et un groupe méthoxy.

6. Composé selon l'une quelconque des revendications 1 à 4, dans lequel Ar³ est choisi dans le groupe constitué par:

7. Composé selon la revendication 1, dans lequel Ar³ a la signification donnée dans la revendication 6, et dans lequel Ar¹ est choisi dans le groupe constitué par le groupe phényle, le groupe 4-hydroxyphényle, le groupe 3,4-dihydroxyphényle, le groupe 3,4-dichlorophényle, le groupe 2-chloro-3,4-dihydroxyphényle, le groupe 2-fluoro-3,4-dihydroxyphényle, le groupe 4-hydroxy-3-méthoxyphényle, le groupe 4-hydroxy-3-hydroxyméthylphényle, le groupe 4-hydroxy-3-(HCONH-)phényle, le groupe 3-chlorophényle, le groupe 2,5-diméthoxyphényle, le groupe 3,5-dichloro-4-aminophényle, et le groupe 2,8-dihydroxyquinoléin-5-yle.

8. Composé selon l'une quelconque des revendications 1 à 7, dans lequel Ar² représente un 1,4-phénylène.

9. Composé selon l'une quelconque des revendications 1 à 8, dans lequel W représente une liaison, un méthylène, un éthylène, un propylène, -(CH₂)₆-O-(CH₂)₃- ou -(CH₂)₆-O-.

10. Composé selon la revendication 9, dans lequel Ar³ représente un groupe phényle ou un groupe 4-hydroxy-3-hydroxyméthylphényle.

11. Composé répondant à la formule:

   où la stéréochimie à *C et à **C est choisie dans le groupe constitué par (RS) et (RS); (RS) et (R); (RS) et (S); (R) et (S); et (R) et (R);
   et des sels pharmaceutiquement acceptables de celui-ci.

12. Composé selon la revendication 11, dans lequel la stéréochimie à *C et à **C est (R) et (R).

13. Composé selon la revendication 1, qui est l'un des composés suivants: trans-1,4-bis{N-[2-(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]amino}cyclohexane; 1,8-bis{N-[2-(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]amino}-p-menthane; 1-{N-[2-(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]aminométhyl}-2-N-[2-(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]amino}benzène; 1-{2-[N-2-[(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]amino]éthyl}-4-{N-[2-(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]amino}benzène; 1-{N-[2-(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]aminométhyl}-4-{N-[2-(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]amino}benzène; 1-{2-(N-2-[(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]amino}éthyl}-4-{N-[2-phényl-2-hydroxyéthyl]amino]benzène; 1-{2-[N-[2-phényl-2-hydroxyéthyl]aminoéthyl}-4-[N-(2-phényl-2-hydroxyéthyl)amino]benzène; 1- {2-[N-2-(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]amino]éthyl}-4-[N-(2-phényl-2-(S)-hydroxyéthyl)amino]benzène; 1-{2-[N-2-(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]amino]éthyl}-4-[N-(2-phényl-2-(R)-hydroxyéthyl)amino]benzène; 1-{2-{N-2-(4-hydroxy-3-hydroxyméthylphényl)-2-(R)-hydroxyéthyl]aminoéthyl}-4-[N-(2-phényl-2-(S)-hydroxyéthyl)amino]benzène; 1-{2-[N-2-(4-hydroxy-3-hydroxyméthylphényl)-2-hydroxyéthyl]amino]éthyl}-4-[N-(2-napth-1-yloxyméthyl-2-hydroxyéthyl)amino]benzène; ou un sel pharmaceutiquement acceptable de celui-ci.

14. Composition pharmaceutique comprenant un vecteur pharmaceutiquement acceptable et une quantité efficace d'un composé selon l'une quelconque des revendications 1 à 13.

15. Composé selon l'une quelconque des revendications 1 à 13 ou composition pharmaceutique selon la revendication 14, destinés à être utilisés en tant que médicament, notamment comme médicament destiné au traitement d'une maladie médiée par un récepteur β₂-adrénergique chez un mammifère.

16. Utilisation d'un composé selon l'une quelconque des revendications 1 à 13 ou d'une composition pharmaceutique selon la revendication 14, dans la fabrication d'un médicament destiné à traiter une maladie médiée par un récepteur β₂-adrénergique chez un mammifère.

17. Composé ou composition selon la revendication 15 ou utilisation selon la revendication 16, dans lesquels le médicament est destiné à traiter une maladie respiratoire, et notamment l'asthme.

Drawing